Muscle injuries, occurring recreationally as well as in the workplace and home, are among the most common musculoskeletal conditions in the U.S. Satellite cells provide muscle with the potential for regeneration, but for large defects, slow healing and excessive proliferation of fibroblasts frequently results in fibrosis and scarring that can create a mechanical barrier that delays or restricts myofibers from bridging the injury gap. Recent findings have begun to elucidate differences between inflammatory processes that promote muscle repair and regeneration following injury and those that disrupt muscle homeostasis. In light of the multiple demands needed for preventing fibrotic scarring, a multidisciplinary team has been assembled to apply a proactive strategy in which multiple biomolecules are delivered in a site-specific and temporally orchestrated manner to treat different aspects of the inflammatory and wound healing processes. Aim 1 will develop and characterize a mechanically flexible controlled release system for localized delivery of anti- inflammatory, anti-oxidant, pro-resolution, and anti-fibrotic biomolecules. With respect to this Aim, it is hypothesized that the devices can be tailored to deliver anti-inflammatory, anti-oxidant pro-resolution, and anti-fibrotic molecules with discrete profiles that roughly follow the kineticsof the wound healing process. Aim 2 will determine the efficacy of controlled, localized, sequential release of anti-inflammatory, anti- oxidant, pro-resolution, and anti-fibrotic components to enhance structural/histological, biochemical, and functional properties in vivo in a rodent skeletal muscle defect model. The working hypothesis is that sequential treatment devices, i.e., materials that resolve inflammation and then prevent fibrosis, will not only enhance muscle regeneration, but these films will be more effective than those releasing only one of the components or that deliver them without regard to the sequence of events during wound healing. Furthermore, the methods may be applicable not only to repair of skeletal muscle defects but also for treatment of many other diseases in which control of inflammation and subsequent wound healing processes is needed. PUBLIC HEALTH RELEVANCE: Muscle injuries, occurring recreationally as well as in the workplace and home, are among the most common musculoskeletal conditions in the U.S. Although muscle has the potential to regenerate, slow healing of large defects frequently results in scarring and incomplete recovery. This project will develop bioerodible films that control different phases of wound healing to enhance muscle regeneration.